Ubiquitin is a small protein present in all eukaryotes (most eukaryotic cells). Ubiquitin consists of 76 amino acids with a molecular weight of approximately 8.451kDa. Its main function is to mark proteins that need to be broken down so that they can be degraded by the 26S proteasome. Some receptors on the regulatory subunits of the 26S proteasome can recognize polyubiquitinated proteins linked at positions K48 and K11, and the 20S core subunit hydrolyzes substrates under the power of ATPase. Ubiquitin can also tag transmembrane proteins and participate in vesicular transport of proteins. Atypical ubiquitin chains play important roles in cell signaling, endocytosis, DNA damage repair and regulation of the NF-κB pathway. It is highly conserved in eukaryotes, with 96% similarity between human and yeast ubiquitin.
Ubiquitination is an important protein post-translational modification process in eukaryotic cells and is involved in a variety of cellular functions by targeting protein degradation or other signaling pathways. The polyubiquitination modification of substrate proteins is a continuous process, which not only involves the participation of enzymes related to the complex ubiquitin system, but also has more complex structural interactions and ubiquitin chain assembly mechanisms. Different ubiquitin chain modifications determine different downstream fates of substrate proteins, and the important role of ubiquitin-conjugating enzyme E2 in the formation of ubiquitin chain has received increasing attention. The in-depth study and understanding of the formation mechanism of ubiquitin chains is conducive to the discovery of disease targets related to the ubiquitin system, which can be treated by ubiquitination regulation methods.
Ubiquitination modifications include monoubiquitination and polyubiquitination. Polyubiquitination modification can be divided into homotypic or heterotypic polyubiquitination modification. In addition, the acetylation and phosphorylation modifications of ubiquitin molecules greatly increase the complexity of ubiquitin chains. The formation of different ubiquitin chains often depends on ubiquitin ligases or deubiquitinases.
Protein ubiquitination has important biological functions. In the process of ubiquitination, ubiquitins can be linked together to form ubiquitin chains. There are seven lysine residues on ubiquitin, all seven lysines can be used to synthesize ubiquitin chains, and ubiquitin chains with different linkages have different functions. Among them, Lys48-linked ubiquitin chains are one of the most well-studied linking methods, which mainly mediate protein degradation, but the synthesis mechanism of Lys48-linked ubiquitin chains in mammals is not yet clear.